A hyperactive signalosome in acute myeloid leukemia drives addiction to a tumor-specific Hsp90 species Journal Article

   

Authors:	Zong, H.; Gozman, A.; Caldas-Lopes, E.; Taldone, T.; Sturgill, E.; Brennan, S.; Ochiana, S. O.; Gomes-DaGama, E. M.; Sen, S.; Rodina, A.; Koren, J. 3rd; Becker, M. W.; Rudin, C. M.; Melnick, A.; Levine, R. L.; Roboz, G. J.; Nimer, S. D.; Chiosis, G.; Guzman, M. L.
Article Title:	A hyperactive signalosome in acute myeloid leukemia drives addiction to a tumor-specific Hsp90 species
Abstract:	Acute myeloid leukemia (AML) is a heterogeneous and fatal disease with an urgent need for improved therapeutic regimens given that most patients die from relapsed disease. Irrespective of mutation status, the development of aggressive leukemias is enabled by increasing dependence on signaling networks. We demonstrate that a hyperactive signalosome drives addiction of AML cells to a tumor-specific Hsp90 species (teHsp90). Through genetic, environmental, and pharmacologic perturbations, we demonstrate a direct and quantitative link between hyperactivated signaling pathways and apoptotic sensitivity of AML to teHsp90 inhibition. Specifically, we find that hyperactive JAK-STAT and PI3K-AKT signaling networks are maintained by teHsp90 and, in fact, gradual activation of these networks drives tumors increasingly dependent on teHsp90. Thus, although clinically aggressive AML survives via signalosome activation, this addiction creates a vulnerability that can be exploited with Hsp90-directed therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Keywords:	signal transduction; leukemia, myeloid, acute; antineoplastic agents; antineoplastic agent; mouse; animal; metabolism; animals; mice; apoptosis; drug screening; pathology; xenograft model antitumor assays; physiology; nude mouse; mice, nude; heat shock protein 90; hsp90 heat-shock proteins; benzodioxoles; purines; purine derivative; 1,3 benzodioxole derivative; acute myeloid leukemia; drug effects; humans; human; antagonists and inhibitors; 9h-purine-9-propanamine, 6-amino-8-((6-iodo-1,3-benzodioxol-5-yl)thio)-n-(1-methylethyl)-
Journal Title:	Cell Reports
Volume:	13
Issue:	10
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2015-12-15
Start Page:	2159
End Page:	2173
Language:	English
DOI:	10.1016/j.celrep.2015.10.073
PUBMED:	26628369
PROVIDER:	scopus
PMCID:	PMC4699804
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85017070647&doi=10.1016%2fj.celrep.2015.10.073&partnerID=40&md5=4c8557e50fb793d66b91d3d7a796cc36
Notes:	Article -- Export Date: 2 May 2017 -- Source: Scopus

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